Medicine and Health Sciences Commons^™

Mobility Task Shows Rescue Of Scotopic Vision In A Swine Model For Autosomal Dominant Retinitis Pigmentosa After Treatment With The Meganuclease Rho 1-2, Gita Jaikumar, Jack Feist, Kautuk Kamboj, Aravind Kumar, Francesca Barone, Archana Jalligampala, Wei Wang, Jeff Smith, Dave Morris, Derek Jantz, Victor Bartsevich, Kristi Viles, Maureen Mccall

Posters-at-the-Capitol

Purpose : Retinitis pigmentosa (RP) is the most common form of inherited retinal disease with ~1:5000 people affected worldwide. The substitution of Proline to Histidine (P23H) at position 23 in the rhodopsin protein is the most common form of adRP in North America. We have shown that treating a transgenic P23H human RHO pig model of adRP (TgP23H hRHO) with a gene-editing meganuclease Rho 1-2, recovers rod structure and restores rod function. We ran WT, Rho1-2 treated and untreated TgP23H hRHO (Tg) pigs through an obstacle course to quantify visually guided mobility under light- and dark-adapted conditions using motion analysis …

Ct-Based Visualization Of Aortic Valve Morphology: From 3d Energy-Integrating Ct To 4d Photon Counting Ct, Alison M. Pouch, Jessie N. Dong, Harold I. Litt, Brittany J. Cannon, Melanie Freas, Victor Ferrari, Thomas G. Gleason, Matthew A. Jolley, Natalie Yushkevich, Jessica Nunez, Jilei Hao, Zaiyang Guo, Shir Goldfinger, John Kelly, Joseph E. Bavaria, Nimesh D. Desai

Division of Cardiology Faculty Papers

BACKGROUND: While 4D contrast-enhanced computed tomography (CT) is used to plan cardiovascular interventions such as transcatheter valve replacement, it is not yet routinely used to characterize minimally calcified aortic valves for planning of surgical valve repair. It is widely recognized that aortic valve morphology has implications for the durability of valve repair surgery.

PURPOSE: The objective is to demonstrate the potential of CT image segmentation for elucidating aortic valve morphology prior to surgery and to illustrate a potential benefit of 4D CT and photon counting CT (PCCT) for patient-specific modeling of dysmorphic aortic valves.

MATERIALS AND METHODS: This observational series …

Neurocognitive Outcomes And Functional Independence In Adult Survivors Of Childhood Medulloblastoma Diagnosed Over 3 Decades, Chiara Papini, Sedigheh Mirzaei, Mengqi Xing, Ingrid Tonning Olsson, Ralph Salloum, Peter M K De Blank, Katharine R Lange, Tricia Z King, Deokumar Srivastava, Wendy M Leisenring, Rebecca M Howell, Kevin C Oeffinger, Leslie L Robison, Gregory T Armstrong, Kevin R Krull, Tara M Brinkman

Faculty, Staff and Student Publications

Background: Treatment of childhood medulloblastoma has evolved to reduce neurotoxicity while improving survival. However, the impact of evolving therapies on late neurocognitive outcomes and adult functional independence remains unknown.

Methods: Adult survivors of childhood medulloblastoma (n = 505; median [minimum-maximum] age, 29 [18-46] years) and sibling controls (n = 727; 32 [18-58] years) from the Childhood Cancer Survivor Study completed surveys assessing neurocognitive problems and chronic health conditions (CHCs). Treatment exposures were categorized as historical (craniospinal irradiation [CSI] ≥ 30 Gy, no chemotherapy), standard-risk (CSI > 0 to < 30 Gy + chemotherapy) and high-risk (CSI ≥ 30 Gy + chemotherapy) therapy. Latent class analysis identified patterns of functional independence using employment, independent living, assistance with routine/personal care needs, driver's license, and marital/partner status. Multivariable models estimated the risk of neurocognitive impairment in survivors versus siblings and by treatment exposure group, and associations between neurocognitive impairment, CHCs, and functional independence.

Results: Survivors in each treatment exposure group had a 4- to 5-fold elevated …

Is Modulation Of Immune Checkpoints On Glioblastoma-Infiltrating Myeloid Cells A Viable Therapeutic Strategy?, Ruochen Du, Jianzhong Zhang, Rimas V Lukas, Shashwat Tripathi, Jared T Ahrendsen, Michael A Curran, Crismita Dmello, Peng Zhang, Roger Stupp, Ganesh Rao, Amy B Heimberger

Faculty, Staff and Students Publications

The field of immunology has traditionally focused on immune checkpoint modulation of adaptive immune cells. However, many malignancies such as glioblastoma are mostly devoid of T cells and rather are enriched with immunosuppressive myeloid cells of the innate immune system. While some immune checkpoint targets are shared between adaptive and innate immunity, myeloid-specific checkpoints could also serve as potential therapeutics. To better understand the impact of immune checkpoint blockade on myeloid cells, we systematically summarize the current literature focusing on the direct immunological effects of PD-L1/PD-1, CD24/Siglec-10, collagen/LAIR-1, CX3CL1/CX3CR1, and CXCL10/CXCR3. By synthesizing the molecular mechanisms and the translational implications, …

Pharmacological Or Genetic Inhibition Of Ltcc Promotes Cardiomyocyte Proliferation Through Inhibition Of Calcineurin Activity, Lynn A C Devilée, Abou Bakr M Salama, Jessica M Miller, Janice D Reid, Qinghui Ou, Nourhan M Baraka, Kamal Abou Farraj, Madiha Jamal, Yibing Nong, Todd K Rosengart, Douglas Andres, Jonathan Satin, Tamer M A Mohamed, James E Hudson, Riham R E Abouleisa

Faculty, Staff and Students Publications

Cardiomyocytes (CMs) lost during ischemic cardiac injury cannot be replaced due to their limited proliferative capacity. Calcium is an important signal transducer that regulates key cellular processes, but its role in regulating CM proliferation is incompletely understood. Here we show a robust pathway for new calcium signaling-based cardiac regenerative strategies. A drug screen targeting proteins involved in CM calcium cycling in human embryonic stem cell-derived cardiac organoids (hCOs) revealed that only the inhibition of L-Type Calcium Channel (LTCC) induced the CM cell cycle. Furthermore, overexpression of Ras-related associated with Diabetes (RRAD), an endogenous inhibitor of LTCC, induced CM cell cycle …

Conformational Switching Of Arp5 Subunit Regulates Ino80 Chromatin Remodeling, Shagun Shukla, Somnath Paul, Jeison Garcia, Yuan Zhong, Sara Sanz Juste, Karissa Beauchemin, Blaine Bartholomew

Faculty, Staff and Student Publications

The INO80 chromatin remodeler is a versatile enzyme capable of several functions, including spacing nucleosomes equal distances apart, precise positioning of nucleosomes based on DNA shape/sequence and exchanging histone dimers. Within INO80, the Arp5 subunit plays a central role in INO80 remodeling, evidenced by its interactions with the histone octamer, nucleosomal and extranucleosomal DNA, and its necessity in linking INO80's ATPase activity to nucleosome movement. We find two distinct regions of Arp5 binding near the acidic pocket of nucleosomes. One region has an arginine anchor that binds nucleosomes and is vital for INO80 mobilizing nucleosomes. The other region has a …

Hyperleukocytosis In A Neuroblastoma Patient After Treatment With Natural Killer T Cells Expressing A Gd2-Specific Chimeric Antigen Receptor And Il-15, Gengwen Tian, Amy N Courtney, Hangjin Yu, Saleh Bhar, Xin Xu, Gabriel A Barragán, Claudia Martinez Amador, Nisha Ghatwai, Michael S Wood, Deborah Schady, Antonino Montalbano, Shantan Reddy, Aoife M Roche, David De La Cerda, Donald Williams Parsons, Erica J Di Pierro, Frederic D Bushman, Andras Heczey, Leonid S Metelitsa

Faculty, Staff and Students Publications

The ability of immune cells to expand numerically after infusion distinguishes adoptive immunotherapies from traditional drugs, providing unique therapeutic advantages as well as the potential for unmanageable toxicities. Here, we describe a case of lethal hyperleukocytosis in a patient with neuroblastoma treated on phase 1 clinical trial (NCT03294954) with autologous natural killer T cells (NKTs) expressing a GD2-specific chimeric antigen receptor and cytokine interleukin 15 (GD2-CAR.15). This patient was the first to be treated on dose level (DL) 5 and the first patient whose product was restimulated with K562-derived artificial antigen-presenting cells (aAPCs) instead of autologous peripheral blood mononuclear cells …

Alzheimer’S Disease: Relationship Of Cognition And Behavior To Neurochemistry, Peter J. Whitehouse

Faculty Scholarship

Alzheimer’s disease is characterized by loss of cells and synapses in specific neural systems. The development of more effective therapies will depend on understanding the relationships between this pathology and the cognitive and behavioral impairments. In this review, focusing primarily on work in our laboratory, we will examine both classic and neuropeptide neurotransmitter systems and will discuss conceptual and methodological problems in relating clinical and biological measures.

Medicaid Expansion Increases Treatment For Patients With Colon Cancer, John Morgan Lyons, Denise M. Danos, Lauren S. Maniscalco, Yong Yi, Omeed Moaven, Xiaocheng Wu, Quyen Chu

School of Medicine Faculty Publications

Introduction: Medicaid expansion (ME) has positively impacted colon cancer screening. ME’s effect on colon cancer treatment is less clear. This study analyses the effect of ME on patterns of colon cancer treatment. Methods: Patients with primary invasive colon cancer were identified using the Louisiana Tumor Registry. Patients diagnosed with colon cancer prior to ME (2014–2015) were compared to those diagnosed after (2017–2018). Coordinate variables were analyzed using Fisher’s exact test. Treatment status was modeled with multivariable logistic regression and the results are reported as adjusted odds ratios. Results: The proportion of uninsured patients decreased following ME (5.5 versus 1.9, p < 0.001), with the greatest reductions among patients between 45 and 54 years old (13.5% to 3.5%, p < 0.0001), African Americans (8.9 to 2.1%, p < 0.0001), and those in high-poverty neighborhoods (7.1 to 2.1%, p < 0.0001). Following ME, all patients with Stage I-III disease were more likely to receive surgery (OR = 1.95; 95%: CI 1.21–3.14)—especially the extremely impoverished (OR = 2.39; 95% CI 1.41–4.02). Young patients with Stage IV colon cancer were more likely to receive chemotherapy (OR-1.6; 95% CI 1.03–2.4). Patients with Stage IV colon cancer were less likely to receive treatment within 30 days of diagnosis (OR = 0.7; 95% CI 0.5–0.9), but, on subset analysis, this was only observed in non-Medicaid patients. Conclusion: ME is associated with increased treatment for patients with colon cancer, and it did not appear to affect time to treatment. However, it seems to affect different subsets of the population differently.

Attributes Of Pediatric Music Therapists: A Qualitative Analysis Of Parent Descriptions., Elizabeth Harman, Kristin Stegenga, Sheri L. Robb

Manuscripts, Articles, Book Chapters and Other Papers

Therapist attributes are known to contribute to positive therapeutic outcomes and are important to effective training and clinical practice. Although well researched in psychology and play therapy, few studies have directly explored music therapist attributes. To explore and understand these descriptions, we conducted a secondary analysis of parent interview data from a multisite trial investigating a music therapist-delivered intervention for young children with cancer and their parents. We used qualitative descriptive analysis to identify music therapists' attributes as described by parents who participated in the intervention. Our inductive analysis of 28 interviews revealed 135 descriptors of music therapists. We discovered …

Transcleral Chemotherapeutic Delivery By Fibrin Sealant In The Treatment Of Retinoblastoma, Christopher Himes

Master's Theses

Retinoblastoma is the most common intraocular cancer in children, accounting for roughly 9,000 new cases each year—claiming the lives of up to 70% of cases in certain regions of the world. While modern retinoblastoma treatments in developed countries have significantly reduced mortality rates, post-treatment consequences such as vision loss, off-site organ dysfunction, and secondary metastases remain unmet clinical needs. Past studies have confirmed transscleral delivery as an efficacious means to achieve high intraocular drug concentrations possibly superior to the standard systemic regimen of vincristine, etoposide, and carboplatin (VEC) for tumor suppression. This led to several studies exploring the use of …

How Are You Doing… Really? A Review Of Whole Person Health Assessments, Kurt C. Stange

Faculty Scholarship

Policy Points A redirection of measurement in health care from a narrow focus on diseases and care processes towards assessing whole person health, as perceived by the person themself, may provide a galvanizing view of how health care can best meet the needs of people and help patients feel heard, seen, and understood by their care team. This review identifies key tensions to navigate as well as four overarching categories of whole person health for consideration in developing an instrument optimized for clinical practice. The categories (body and mind, relationships, living environment and finances, and engagement in daily life) include …

Sitravatinib In Combination With Nivolumab Plus Ipilimumab In Patients With Advanced Clear Cell Renal Cell Carcinoma: A Phase 1 Trial, Pavlos Msaouel, Kai Yu, Ying Yuan, Jianfeng Chen, Xinmiao Yan, Menuka Karki, Fei Duan, Rahul A Sheth, Priya Rao, Kanishka Sircar, Amishi Y Shah, Amado J Zurita, Giannicola Genovese, Min Li, Chih-Chen Yeh, Minghao Dang, Guangchun Han, Yanshuo Chu, Max Hallin, Peter Olson, Rui Yang, Daniela Slavin, Hirak Der-Torossian, Curtis D Chin, Nizar M Tannir, Linghua Wang, Jianjun Gao

Faculty, Staff and Student Publications

We conducted a phase I trial to determine the optimal dose of triplet therapy with the tyrosine kinase inhibitor sitravatinib plus nivolumab plus ipilimumab in 22 previously untreated patients with advanced clear cell renal cell carcinoma. The primary endpoint was safety. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), 1-year survival probability, and sitravatinib pharmacokinetics. Sitravatinib dose of 35 mg daily plus nivolumab 3 mg/kg and ipilimumab 1 mg/kg resulted in high frequency of immune-related adverse events. Subsequent dose reduction of ipilimumab to 0.7 mg/kg allowed safe …

Integrating Ctla-4/Pd-1 Blockade Into Cervical Cancer Management: Results Of Compassion-16, Jeffrey A How, Amir A Jazaeri

Faculty, Staff and Student Publications

Although there is anti-tumor efficacy of dual CTLA-4/PD-1 blockade in advanced/recurrent cervical cancer, it is unclear whether combination with chemotherapy is synergistic. In COMPASSION-16, Wu et al. demonstrated improved survival outcomes of cadolinimab plus chemotherapy compared to chemotherapy alone for first-line systemic therapy for advanced/recurrent cervical cancer, suggesting a potential role of bispecific CTLA-4/PD-1 inhibitors in the frontline setting.

Pembrolizumab Plus Chemotherapy In Frontline Treatment Of Advanced Ovarian Cancer: Clinical And Translational Results From A Phase 2 Trial, Jeffrey A How, Minghao Dang, Sanghoon Lee, Bryan Fellman, Shannon N Westin, Anil K Sood, Nicole D Fleming, Aaron Shafer, Ying Yuan, Jinsong Liu, Li Zhao, Joseph Celestino, Richard Hajek, Margaret B Morgan, Edwin R Parra, Caddie D Laberiano Fernandez, Claudio A Arrechedera, Luisa Maren Solis Soto, Kathleen M Schmeler, Alpa Nick, Karen H Lu, Robert Coleman, Linghua Wang, Amir A Jazaeri

Faculty, Staff and Student Publications

Background: The efficacy and feasibility of pembrolizumab combined with chemotherapy in frontline management of advanced high-grade epithelial ovarian cancer (EOC) is unknown. Additionally, modification of the tumor microenvironment following neoadjuvant therapy is not well understood.

Methods: In this single-arm phase 2 trial (this study was registered at ClinicalTrials.gov: NCT02520154), eligible patients received up to 4 cycles of neoadjuvant chemotherapy followed by interval cytoreduction, 3 cycles of adjuvant intravenous carboplatin/weekly paclitaxel/pembrolizumab, and finally maintenance pembrolizumab until progression or toxicity (maximum 20 cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included feasibility, toxicity, and overall survival (OS). PD-L1 staining, …

Residual Traditional Risk In Non-Traditional Atherosclerotic Diseases, Federico Biscetti, Giorgia Polito, Maria Margherita Rando, Maria Anna Nicolazzi, Luis H. Eraso, Paul J. Dimuzio, Massimo Massetti, Antonio Gasbarrini, Andrea Flex

Department of Surgery Faculty Papers

Individuals with chronic inflammatory and immune disorders are at an increased risk of atherosclerotic events and premature cardiovascular (CV) disease. Despite extensive literature exploring the relationship between "non-traditional" atherosclerotic conditions and CV risk, many aspects remain unresolved, including the underlying mechanisms promoting the "non-traditional CV risk", the development of an innovative and comprehensive CV risk assessment tool, and recommendations for tailored interventions. This review aims to evaluate the available evidence on key "non-traditional" CV risk-enhancer conditions, with a focus on assessing and managing CV risk factors. We conducted a comprehensive review of 412 original articles, narrative and systematic reviews, and …

Developing Real-Time, Online Beam Control Of Uhdr Irradiators To Facilitate Flash Translational Investigations, Austin M. Sloop

Dartmouth College Ph.D Dissertations

The field of radiation oncology seeks novel techniques to increase the therapeutic ratio to treat malignancies while minimizing damage and toxicities in healthy tissues. While it was observed that delivering therapeutic doses at high dose rate could elicit lower biological effects over a half-century ago, the field of ultra-high dose rate (UHDR) radiation therapy (colloquially known as FLASH RT) has seen a resurgence in recent years due to an alignment of accelerator capability, dosimetric advances, and improved biotechnological techniques. This has opened the door to studying potential underlying mechanisms such that we may leverage the effects of FLASH tissue sparing …

Superstable Lipid Vacuoles Endow Cartilage With Its Shape And Biomechanics, Raul Ramos, Kim T Pham, Richard C Prince, Leith B Leiser-Miller, Maneeshi S Prasad, Xiaojie Wang, Rachel C Nordberg, Benjamin J Bielajew, Jerry C Hu, Kosuke Yamaga, Ji Won Oh, Tao Peng, Rupsa Datta, Aksana Astrowskaja, Axel A Almet, John T Burns, Yuchen Liu, Christian Fernando Guerrero-Juarez, Bryant Q Tran, Yi-Lin Chu, Anh M Nguyen, Tsai-Ching Hsi, Norman T-L Lim, Sandra Schoeniger, Ruiqi Liu, Yun-Ling Pai, Chella K Vadivel, Sandy Ingleby, Andrew E Mckechnie, Frank Van Breukelen, Kyle L Hoehn, John J Rasweiler, Michinori Kohara, William J Loughry, Scott H Weldy, Raymond Cosper, Chao-Chun Yang, Sung-Jan Lin, Kimberly L Cooper, Sharlene E Santana, Jeffrey E Bradley, Michael A Kiebish, Michelle Digman, David E James, Amy E Merrill, Qing Nie, Thomas F Schilling, Aliaksandr A Astrowski, Eric O Potma, Martín I García-Castro, Kyriacos A Athanasiou, Richard R Behringer, Maksim V Plikus

Faculty, Staff and Student Publications

Conventionally, the size, shape, and biomechanics of cartilages are determined by their voluminous extracellular matrix. By contrast, we found that multiple murine cartilages consist of lipid-filled cells called lipochondrocytes. Despite resembling adipocytes, lipochondrocytes were molecularly distinct and produced lipids exclusively through de novo lipogenesis. Consequently, lipochondrocytes grew uniform lipid droplets that resisted systemic lipid surges and did not enlarge upon obesity. Lipochondrocytes also lacked lipid mobilization factors, which enabled exceptional vacuole stability and protected cartilage from shrinking upon starvation. Lipid droplets modulated lipocartilage biomechanics by decreasing the tissue's stiffness, strength, and resilience. Lipochondrocytes were found in multiple mammals, including humans, …

Molecular Dynamics At Immune Synapse Lipid Rafts Influence The Cytolytic Behavior Of Car T Cells, Ahmed Z Gad, Jessica S Morris, Lea Godret-Miertschin, Melisa J Montalvo, Sybrina S Kerr, Harrison Berger, Jessica C H Lee, Amr M Saadeldin, Mohammad H Abu-Arja, Shuo Xu, Spyridoula Vasileiou, Rebecca M Brock, Kristen Fousek, Mohamed F Sheha, Madhuwanti Srinivasan, Yongshuai Li, Arash Saeedi, Kandice R Levental, Ann M Leen, Maksim Mamonkin, Alexandre Carisey, Navin Varadarajan, Meenakshi Hegde, Sujith K Joseph, Ilya Levental, Malini Mukherjee, Nabil Ahmed

Faculty, Staff and Students Publications

Chimeric antigen receptor T cells (CART) targeting CD19 through CD28.ζ signaling induce rapid lysis of leukemic blasts, contrasting with persistent tumor control exhibited by 4-1BB.ζ-CART. We reasoned that molecular dynamics at the CART immune synapse (CARIS) could explain differences in their tumor rejection kinetics. We observed that CD28.ζ-CART engaged in brief highly lethal CARIS and mastered serial killing, whereas 4-1BB.ζ-CART formed lengthy CARIS and relied on robust expansion and cooperative killing. We analyzed CARIS membrane lipid rafts (mLRs) and found that, upon tumor engagement, CD28.ζ-CAR molecules rapidly but transiently translocated into mLRs, mobilizing the microtubular organizing center and lytic granules …

Peripheral Extracellular Vesicles For Diagnosis And Prognosis Of Resectable Lung Cancer: The Lucex Study Protocol, Jorge Rodríguez-Sanz, Nadia Muñoz-González, José Pablo Cubero, Pablo Ordoñez, Victoria Gil, Raquel Langarita, Myriam Ruiz, Marta Forner, Marta Marín-Oto, Elisabet Vera, Pedro Baptista, Francesca Polverino, Juan Antonio Domingo, Javier García-Tirado, José María Marin, David Sanz-Rubio

Faculty, Staff and Students Publications

Background/Objectives: Lung cancer is the primary cause of cancer-related deaths. Most patients are typically diagnosed at advanced stages. Low-dose computed tomography (LDCT) has been proven to reduce lung cancer mortality, but screening programs using LDCT are associated with a high number of false positives and unnecessary thoracotomies. It is therefore imperative that a certain diagnosis is refined, especially in cases of solitary pulmonary nodules that are difficult to technically access for an accurate preoperative diagnosis. Extracellular vesicles (EVs) involved in intercellular communication may be an innovative biomarker for diagnosis and therapeutic strategies in lung cancer, regarding their ability to carry …

Building Toward Population Reserve And A Critical Positive Psychiatry, Peter J. Whitehouse

Faculty Scholarship

No abstract provided.

Microrna 133a Regulates Squalene Epoxidase Expression In Colorectal Cancer Cells To Control Cell Proliferation And Cholesterol Production, Ji Su Mo, Santosh Lamichhane, Grinsun Sharma, Soo Cheon Chae

School of Medicine Faculty Publications

Background/Objectives: Colorectal cancer (CRC) is one of the most common cancers worldwide, with high incidence and mortality rates. MicroRNAs are endogenous and non-coding RNAs that play a pivotal role in the development and progression of various cancers by targeting specific genes. Previously, we identified MIR133A to be significantly decreased in human CRC tissues. This study aims to identify the relationship with SQLE, one of the candidate target genes of MIR133A, and study their interaction in CRC cells. Methods: Through the luciferase reporter assay, quantitative RT-PCR (qRT-PCR), and Western blot analysis. Results: We identified SQLE as a direct target gene of …

A Β-Hydroxybutyrate Shunt Pathway Generates Anti-Obesity Ketone Metabolites, Maria Dolores Moya-Garzon, Mengjie Wang, Veronica L Li, Xuchao Lyu, Wei Wei, Alan Sheng-Hwa Tung, Steffen H Raun, Meng Zhao, Laetitia Coassolo, Hashim Islam, Barbara Oliveira, Yuqin Dai, Jan Spaas, Antonio Delgado-Gonzalez, Kenyi Donoso, Aurora Alvarez-Buylla, Francisco Franco-Montalban, Anudari Letian, Catherine P Ward, Lichao Liu, Katrin J Svensson, Emily L Goldberg, Christopher D Gardner, Jonathan P Little, Steven M Banik, Yong Xu, Jonathan Z Long

Children’s Nutrition Research Center Staff Publications

β-Hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve the interconversion of BHB and primary energy intermediates. Here, we identify a previously undescribed BHB secondary metabolic pathway via CNDP2-dependent enzymatic conjugation of BHB and free amino acids. This BHB shunt pathway generates a family of anti-obesity ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. The most abundant BHB-amino acid, BHB-Phe, is a ketosis-inducible congener of Lac-Phe that activates hypothalamic and brainstem neurons and suppresses feeding. Conversely, CNDP2-KO mice exhibit …

Perinuclear Organelle Trauma At The Nexus Of Cardiomyopathy Pathogenesis Arising From Loss Of Function Lmna Mutation, Jason C. Choi

Center for Translational Medicine Faculty Papers

Over the past 25 years, nuclear envelope (NE) perturbations have been reported in various experimental models with mutations in the LMNA gene. Although the hypothesis that NE perturbations from LMNA mutations are a fundamental feature of striated muscle damage has garnered wide acceptance, the molecular sequalae provoked by the NE damage and how they underlie disease pathogenesis such as cardiomyopathy (LMNA cardiomyopathy) remain poorly understood. We recently shed light on one such consequence, by employing a cardiomyocyte-specific Lmna deletion in vivo in the adult heart. We observed extensive NE perturbations prior to cardiac function deterioration with collateral damage in the …

Author Correction: Best Practice Advice For Asthma Exacerbation Prevention And Management In Primary Care: An International Expert Consensus, Neil Skolnik, Barbara P. Yawn, Jaime Correia De Sousa, María Mar Martínez Vázquez, Amanda Barnard, Wendy L. Wright, Austin Ulrich, Tonya Winders, Stephen Brunton

Department of Family & Community Medicine Faculty Papers

No abstract provided.

Alleviation Of Liver Fibrosis By Inhibiting A Non-Canonical Atf4-Regulated Enhancer Program In Hepatic Stellate Cells, Li-Xian Yang, Chuangye Qi, Si Lu, Xiang-Shi Ye, Parnaz Merikhian, Du-Yu Zhang, Tao Yao, Jiang-Sha Zhao, Ying Wu, Yongshi Jia, Bo Shan, Jinghai Chen, Xiaozhou Mou, Jia You, Wenbo Li, Yu-Xiong Feng

Faculty, Staff and Student Publications

Liver fibrosis is a critical liver disease that can progress to more severe manifestations, such as cirrhosis, yet no effective targeted therapies are available. Here, we identify that ATF4, a master transcription factor in ER stress response, promotes liver fibrosis by facilitating a stress response-independent epigenetic program in hepatic stellate cells (HSCs). Unlike its canonical role in regulating UPR genes during ER stress, ATF4 activates epithelial-mesenchymal transition (EMT) gene transcription under fibrogenic conditions. HSC-specific depletion of ATF4 suppresses liver fibrosis in vivo. Mechanistically, TGFβ resets ATF4 to orchestrate a unique enhancer program for the transcriptional activation of pro-fibrotic EMT genes. …

Risk-Stratified Venous Thromboembolism Chemoprophylaxis After Total Joint Arthroplasty: Evaluation Of An Institutional Approach., Sara J Hyland, Maria J Fada, Michelle Secic, Robert A Fada, Marie M Lockhart, Richard H Parrish

OhioHealth Research Institute Articles

No abstract provided.

The Impact Of Fibular Fixation Method On Pilon Fracture Healing., Anthony Perugini, Scott Hyland, James Iandoli, Zachary Hill, John Peabody, Daniel Degenova, Mallory Faherty, Benjamin Taylor

OhioHealth Research Institute Articles

No abstract provided.

Functional Characterization Of Qt Interval Associated Scn5a Enhancer Variants Identify Combined Additive Effects, Lavanya Gunamalai, Parul Singh, Brian Berg, Leilei Shi, Ernesto Sanchez, Alexa Smith, Ghislain Breton, Mark T Bedford, Darius Balciunas, Ashish Kapoor

Faculty, Staff and Student Publications

Several empirical and theoretical studies suggest the presence of multiple enhancers per gene that collectively regulate gene expression, and that common sequence variation impacting on the activities of these enhancers is a major source of inter-individual gene expression variability. However, for the vast majority of genes, enhancers and the underlying regulatory variation remains unknown. Even for the genes with well-characterized enhancers, the nature of the combined effects from multiple enhancers and their variants, when known, on gene expression regulation remains unexplored. Here, we have evaluated the combined effects from five SCN5A enhancers and their regulatory variants that are known to …

Neoadjuvant Or Concurrent Atezolizumab With Chemoradiation For Locally Advanced Cervical Cancer: A Randomized Phase I Trial, Jyoti Mayadev, Dmitriy Zamarin, Wei Deng, Heather A. Lankes, Giulio Pesci, Hayeon Kim, Junzo P. Chino, Barbara Banbury, Ned Sherry, Elad Sharon, Sharad A. Ghamande, Catherine Ferguson, Loren Mell, Laura Holman, Cara Mathews, David O'Malley, Alexander Olawaiye, Elizabeth Hopp, Charles Leath, Larry Copeland, Robert Mannel, Roisin O'Cearbhaill, Carol Aghajanian, Russell J. Schilder

Department of Medical Oncology Faculty Papers

Combined immune checkpoint blockade (ICB) and chemoradiation (CRT) is approved in patients with locally advanced cervical cancer (LACC) but optimal sequencing of CRT and ICB is unknown. NRG-GY017 (NCT03738228) was a randomized phase I trial of atezolizumab (anti-PD-L1) neoadjuvant and concurrent with CRT (Arm A) vs. concurrent with CRT (Arm B) in patients with high-risk node-positive LACC. The primary endpoint was the fraction of expanded tumor-associated T-cell receptor (TCR) clones in blood at day 21 as a surrogate measure of anti-tumor immune response. Secondary objectives were safety and feasibility, 2-year disease-free survival (DFS), and predictive value of PD-L1 expression. Forty …